Abstract Disease modification is the primary unmet need in Parkinson's disease (PD) therapeutics. Currently clinical trials of promising candidate neuroprotectants are limited by the inefficiency and imprecision of repeated in- person clinical assessments required of people with Parkinson's who volunteer to participate in these studies. Emerging telemedicine and smartphone-based remote sensor assessments provide opportunities to help overcome these obstacles and improve prospects for the success of future trials. Demonstrating the utility of these relatively inexpensive accessible tele-health platforms for the measurement of PD progression would also establish infrastructure for long-term follow up of participants after completion of interventional studies. STEADY-PD3 and SURE-PD3 are active NINDS-funded phase 3 trials of potential disease-modifying interventions in PD. Both studies, comprising ~600 early PD subjects, include biomarker sub-studies collecting DNA and serial plasma samples and in a subset serial dopamine transporter (DAT) neuroimaging data that will become part of the Parkinson's Disease Biomarker Program (PDBP). The objective of this proposal is to leverage modern technology to develop, pilot and implement a 100% virtual model for long-term follow up utilizing telemedicine and smartphone platforms for quantitative monitoring of clinician- and patient-reported outcomes. Specific Aim (SA) 1 is to establish infrastructure for longitudinal remote follow up of phase 3 trial cohorts; a) transitioning from site-based to a centralized coordination center to manage all subject activity, b) conducting an annual telemedicine research visit (tele-visit) program, and c) implementing a smartphone data collection platform tailored to a clinical trial cohort. SA2 is to compare smartphone (patient-driven) vs tele-visit (clinician-driven) outcomes by a) correlating these platforms' component and composite features, and their changes over years, and b) comparing their abilities to i) measure PD progression; ii) distinguish rapid vs slow progressors based on baseline motor scale scores, DAT deficit or serum urate levels; and iii) demonstrate persistence of any effects of isradipine or inosine in their respective trials. SA3 is to explore novel smartphone- based real-life mobility biomarkers of PD disability and its progression that are normally inaccessible with traditional office measures. The ability of passively collected smartphone data, on ambulation and location, to enable assessments of physical activity and socialization that meaningfully integrate motor and non-motor functions will be investigated. This project leverages the major phase 3 trial investments of NIH and study subjects by extending their follow up to establish the utility of tele-health metrics for tracking PD progression in clinical cohorts. Its results are expected to accelerate effective testing of a greater number of promising candidates for disease modification. The results will have an immediate impact on the rational selection of smartphone versus tele-visit monitoring in designing the next generation of PD trials, and may help identify and substantiate novel digital as well as molecular biomarkers of PD.